ABSTRACT Lewy body dementia (LBD) is a prevalent disorder that is characterized by impaired attention and executive function, visual hallucinations, parkinsonian features, sleep difficulty, and worse functional and survival outcomes than Alzheimer's disease (AD) or Parkinson's disease (PD). The two clinical entities of LBD, Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB), are heterogeneous. Although they share a common neuropathological finding, namely Lewy pathology, they have variable disease courses and treatment strategies. Yet current diagnostic procedures to distinguish these subtypes are imprecise and thus pose an important challenge for timely clinical diagnosis and for research. We will therefore leverage existing resources (e.g., postmortem brain tissue, DNA samples, genotypes, and methylome data) to advance the discovery of unique peripheral biomarkers for DLB and PDD. Epigenetic modifications have been identified as capable of altering transcriptional activity across multiple genes and biological pathways. A state-of-the-art technological method known as whole- genome bisulfite sequencing (WGBS) has been used to construct methylome maps for human cells and provides unbiased interrogation of the approximately 3 million quantifiable CpG sites. The detection of disease-dependent DNA methylation patterns that are concordant between peripheral blood leukocytes (PBLs) and postmortem brain (PMB) tissue in PD suggests that methylation profiles may serve as a readily accessible biomarker for LBD. However, previous studies did not include genome-wide interrogation. We thus propose the following 3 aims to identify unique epigenetic profiles in LBD. Aim 1. Generate whole-methylome from the PMBs and PBLs of LBD subjects using WGBS. We will perform whole-methylome sequencing in frontal cortical and PBL samples selected from a well- characterized national LBD consortium and the University of Washington Neuropathology Core. Aim 2. Define differentially methylated regions (DMRs) that are specifically associated with LBD. We will detect concordant methylation profiles in LBD, thereby identifying potential peripheral biomarkers that serve as a good proxy for methylation alterations in the brain. Aim 3. Validate DMRs identified in Aim 2 in additional PBL samples using targeted bisulfite sequencing. We will verify our findings in samples selected from the National Alzheimer's Coordinating Center and the PDBP. We hypothesize that we will identify concordant methylation alterations in brain and blood in LBD, and we expect that a subset of these DMRs will be verified in additional PBLs. These findings will thereby constitute novel sources for biomarker discovery and development in accessible tissue.